Idiopathic myelofibrosis (IM) is a Philadelphia chromosome negative myeloproliferative disorder (MPD) thought to originate at the level of the muKipotent hematopoietic stem cell. The peripheral blood (PB) of IM patients contain greater numbers of hematopoietic stem cells (HSC) and progenitor cells (HPC) as well as endothelial progenitor cells (EPC) than normal individiduals. Since it is possible that the abnormal HSC/HPC/EPC trafficking in IM could be attributed to multiple pathological events, acting either alone or in combination, we intend to explore this pathological process by addressing the following hypotheses and objectives: Specific Aim 1: We will test the hypothesis that the abnormal CD34+ cell trafficking in IM is a consequence of defects in IM HSC/HPC/EPC that compromises the ability of these cells to be retained within the BM. Specific Aim 2: We will test the hypothesis that the abnormal CD34+ cell trafficking in IM is a consequence of the continuous release of proteases from IM BM HSC/HPC/EPC or their cellular progeny, which render the BM stem cell and/or vascular niches that maintain normal HSC/HPC/EPC homeostasis functionally defective. Since this abnormal HSC/HPC/EPC trafficking appears to be an integral part of the pathobiology of IM, we anticipate that greater understanding of this pathologic process will lead to the identification of therapeutic targets in the future against which novel drugs might be directed, allowing for improved treatment of IM, as well as the identification of additional biomarkers that might serve as indicators of disease activity. In addition, further insight into this pathological condition may also advance our understanding of normal HSC/HPC/EPC trafficking as well as cytokine-induced stem cell mobilization. Relevance: IM is a frequently fatal hematologic malignancy which is associated with increasing numbers of stem cells being present in the PB. We will attempt to dissect the causes of this abnormal HSC trafficking . Insight into this process will provide new targets for the development of therapeutic agents which will prevent the progression of the disease.